Therapeutic microfoam

ABSTRACT

Improved therapeutic sclerosing microfoams are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

[0001] The present invention relates to the generation of microfoamcomprising a sclerosing material, particularly a sclerosing liquid,which is suitable for use in the treatment of various medical conditionsinvolving blood vessels, particularly varicose veins and other disordersinvolving venous malformation.

[0002] Sclerosis of varicose veins is based on the injection into theveins of liquid sclerosant substances which, by inter alia causing alocalized inflammatory reaction, favor the elimination of these abnormalveins. When a sclerosing substance is injected in liquid form, it ismixed with the blood contained in the vein and is diluted in an unknownproportion. The results are uncertain, owing to over- or under-dosage,and are limited to short varicose segments. As the size of the varicoseveins to be injected decreases, this dilution is less and the resultsobtained are more predictable.

[0003] Until recently, sclerosis was a technique selected in cases ofsmall and medium varicose veins, those with diameters equal to orgreater than 7 mm being treated by surgery. Sclerosis and surgerycomplemented one another but sclerosis treatment continued not to beapplicable to large varicose veins. In these large varicose veins, if asclerosing substance was injected, its concentration in the vein, itshomogeneous distribution in the blood, and the time for which it is incontact with the internal walls of the vessel treated were not known.

[0004] In 1946, Orbach injected a few cubic centimeters of air intosmall varicose veins and confirmed a displacement of the blood insidethe vessel which was occupied by the injected air. A sclerosing solutionintroduced immediately afterwards was more effective than if it had beeninjected into the blood. However, in thick varicose veins, when air isinjected the phenomenon described of the displacement of the blood bythe injected air does not occur but the air forms a bubble inside thevein which makes the method ineffective in these vessels.

[0005] The same author had the idea, a few years later, of injectingfoam obtained by agitation of a container containing sodium tetradecylsulfate, which is an anionic sclerosing detergent with a good foamingcapability. The method was of little use owing to the large size of thebubbles formed and was dangerous owing to the side effects ofatmospheric nitrogen which is only slightly soluble in blood. Bothmethods had limited practical repercussion being used only in smallvaricose veins.

[0006] An injectable microfoam suitable for therapeutic uses has nowbeen developed and is described in EP 0656203 and U.S. Pat. No.5,676,962 (incorporated herein by reference). These patents describe amicrofoam produced with a sclerosing substance which, when injected intoa vein, displaces blood and ensures that the sclerosing agent contactsthe endothelium of the vessel in a known concentration and for acontrollable time, achieving sclerosis of the entire segment occupied.

[0007] The advantages of use of this foam are that it allows theconcentration of the sclerosing agent in the blood vessel to be known,since the microfoam displaces the blood and is not diluted therein in tothe same extent as a simple liquid would be. Furthermore it allowshomogeneous distribution of the sclerosis product in the vein to beensured and the time for which it is kept in contact with the internalwalls of the vein to be controlled. None of which factors is knownprecisely or is controllable with the use of sclerosing agents in simpleliquid form.

[0008] The preparation of such a microfoam may be carried out with asolution of any sclerosing substance, particularly polidocanol, alkalimetal tetradecyl sulfate e.g. sodium salt. hypertonic glucose orgluco-saline solutions, chromic glycerol, ethanolamine oleate, sodiummorrhuate or iodic solutions.

[0009] However, this known method requires production of microfoam bythe physician, pharmacist or an assistant immediately prior toadministration to the patient. Such procedure allows for variation ofagent depending upon the person preparing it, with content of gas,bubble size and stability all needing attention with respect to thecondition being treated. It also requires a high degree of care andknowledge that may be difficult to replicate under pressure, i.e. whentime available to prepare the foam is short.

[0010] The method particularly described in the aforesaid patents uses ahigh speed beating action with a brush to generate a foam of correctproperty. Other reported techniques in use do not produce such uniform,stable or injectable microfoam and notably include those where as isbubbled. e.g. sparged into the sclerosant, e.g. by leakage into asclerosant filled syringe from around the side of the syringe plunger.

[0011] Furthermore, a problem in using air as the as for producing thefoam is the perception that large volumes of nitrogen should notunnecessarily be introduced into patients, particularly where largevessels are being filled with foam and eliminated. Gas embolism withnitrogen remains a possibility.

[0012] The solubility of physiological gases in aqueous fluids, such asblood, varies considerably. Thus while nitrogen is almost twice asinsoluble in water as oxygen at STP, carbon dioxide is over fifty timesas soluble in aqueous liquids as nitrogen and over twenty five times assoluble as oxygen. TABLE 1 Solubility of Gases in water at STP Gas MoleFraction Solubility 10⁻⁵ Helium 0.7 Nitrogen 1.18 Oxygen 2.3 Xenon 7.9Nitrous oxide 43.7 Carbon dioxide 61.5

[0013] At the present time it is perceived that production of suchmicrofoam with gases incorporating high proportions of gas that isreadily dispersed in blood, such as carbon dioxide, would be desirablefor the purposes of minimizing the prospect of the treatment producing agas embolism. However, it is also perceived by practitioners that thisis difficult task due to its high solubility in water.

[0014] It would also be desirable to provide a relatively stablemicrofoam of uniform character that is readily producible by use of arelatively simple and reliable mechanism, rather than one involving useof high speed mixing or beating, the time of performance of which mayaffect foam property.

[0015] It is particularly desirable that the microfoam so produced maybe passed through a needle of gauge suitable for injecting into bloodvessels without being significantly converted back to its separate gasand liquid components and/or changing characteristics such assignificantly increasing bubble sizes.

[0016] Such a needle may be of very small diameter, e.g. a 30 gaugeneedle (0.14 mm interior diameter). More typically it will be largere.g. an 18 to 2 gauge needle (interior diameter 0.838 to 0.394 mm), morepreferably 19 to 21 gauge (interior diameter. 0.686 mm).

[0017] The rate at which the foam is passed down the needle can be suchthat any foam might be broken down, but it is desirable that a foam isproduced that does not break down under normal injection conditions,i.e. at rates compatible with control of entry of foam into a vein. Forexample, it should withstand injection at rates of 0.1 to 0.5 mL/second,more preferably 0.3 to 1 mL/second for a 19 to 21 gauge needle.

[0018] It is still further desirable to provide a device that is ofsterile type with regard to the foam it generates particularly withregard to micro-organisms and pyrogens.

[0019] It is particularly desirable to provide a sealed device thatoperates to produce foam of set property suitable for a given medicalprocedure without technical input from the physician who will performthe procedure, or assistants thereof.

[0020] One form of device that could potentially provide these desiredproperties would be an aerosol dispenser of a type that produces foams.However, for the purposes of generating a microfoam to be injected intoa human or animal body, it is undesirable to have a propellant gas ofthe type usually employed in aerosol canisters, e.g. such as isopropane.This determines that the gas from which the foam is to be made mustitself be pressurized to allow production of foam.

[0021] Water soluble gases such as carbon dioxide have been found by theinventors to be incapable of producing a stable foam when generated bymerely being passed through a standard aerosol valve under pressure,such as might be expected to convert a detergent solution such as one ofpolidocanol or sodium tetradecylsulfate to a foam. They have determinedthat when this as is used under pressure to propel a sclerosing agentsolution through a conventional aerosol valve the foam produced, whileinitially containing at least some microfoam structure, is notsufficiently stable to be applied to the treatment of blood vessels asdescribed in EP 0656203 and U.S. Pat. No. 5,676,962. Such foam isfurthermore incapable of being passed through a syringe needle withoutsignificant reversion to liquid and gas phases. It will be realized bythose skilled in the art that the microfoam technique exploits theability of the gas to deliver the sclerosant solution to the wall of thevessel to be treated, rather than to allow its dilution in blood as inthe liquid phase.

[0022] Aerosol units that are capable of producing foam have beendescribed in the prior art. U.S. Pat. No. 3,471,064 describes a devicewherein air is drawn into a foamable liquid through a series of smallholes in the dip tube of the unit. Such a device is not sterile inoperation as it relies on its contents being open to the air. Foam soproduced would appear to vary in properties dependent upon how much airis drawn in. A further device is described in U.S. Pat. No. 3,428,222and utilizes a wicking and foaming element in a compressible containerthat again draws in air to produce foam.

[0023] U.S. Pat. No. 3,970,219 describes sealed aerosol devices whichare capable of using pharmacologically inert gases to foam and expelliquid compositions, It describes devices which produce foam by passageof the propellant through a material having pores of 0.01 to 3 mmdiameter from a lower propellant gas holding chamber to an upper foamholding chamber. The liquid to be foamed sits in the upper chamber or isabsorbed onto the porous material by shaking the container or is wickedup from a lower chamber. This patent teaches that liquid from foam inthe upper chamber drains down into the lower chamber, such that thethinnest walled bubbles are expelled, and teaches that the propellantgas should be ‘less soluble’, such as nitrogen, fluorocarbon orhydrocarbon, where aqueous liquids are to be foamed.

[0024] Similar bubbler devices are used in accessories for use with‘environmentally friendly’ aerosol devices that operate using air underlow pressure, i.e. hand pump conditions. Two such devices are suppliedby Airspray International as the ‘Airspray™ Finger Pump Foamer’ and‘Airspray Mini-Foamer’. The former is said to be suitable for simplewater based formulations while the latter is suggested for cosmetics,hair or skin care preparations. A second such device is provided as anoptional extra in the Swedspray/Eurospray™ hand pump device as a foamingnozzle. This device is marketed as being suitable for use to ‘make youown cleansing foam or shaving lather’.

[0025] However, the present inventors have found that use of theavailable hand-pump devices themselves, which in any case are notsterile, cannot produce good microfoam with high loadings of carbondioxide due to outgassing, nor with inclusion of significant amounts ofglycerol which otherwise stabilizes microfoam. Furthermore, whensignificant back-pressure is applied to the outlet of such device, suchas when attached to a syringe to be loaded for injecting the foam,stuttering occurs. Use of low ejection velocity with this device cancause wetting at the nozzle which results in large bubbles caused by airentrapment. In any case the foams so produced, whether with oxygen orcarbon dioxide, tend to be very dry, with resultant need for highconcentration of sclerosant to be included, and tendency to break up onpassage down a needle.

[0026] It is preferred not to unnecessarily use high concentrations ofsclerosant in the solution as this could result in overdosage should adispensing device fail and deliver a more dense microfoam, i.e.including a higher proportion of liquid than intended.

[0027] Thus there is a need to provide a method and device that arecapable of producing a uniform injectable microfoam made with arelatively low concentration of a sclerosing agent and a significantamount of a blood dispersible gas in sterile fashion without volatileliquid propellants or the need for the operator to directly be concernedin control of its parameters.

[0028] The present applicants have now provided a method and devicescapable of addressing at least some of the aforesaid needs and haveproduced a novel stable injectable sclerosing microfoam with that methodand devices.

[0029] For the purpose of this application terms have the followingdefinitions: Physiologically acceptable blood dispersible gas is a asthat is capable of being substantially completely dissolved in orabsorbed by blood. A sclerosant liquid is a liquid that is capable ofsclerosing blood vessels when injected into the vessel lumen.Scleropathy or sclerotherapy relates to the treatment of blood vesselsto eliminate them. An aerosol is a dispersion of liquid in gas. A majorproportion of a gas is over 50% volume/volume. A minor proportion of agas is under 50% volume/volume A minor amount of one liquid in anotherliquid is under 50% of the total volume. Atmospheric pressure and barare 1000 mbar gauge. Half-life of a microfoam is the time taken for halfthe liquid in the microfoam to revert to unfoamed liquid phase.

[0030] In a first aspect of the present invention there is provided amethod for producing a microfoam suitable for use in scleropathy ofblood vessels, particularly veins, characterized in that it comprisespassing a mixture of a physiologically acceptable blood dispersible asand an aqueous sclerosant liquid through one or more passages having atleast one cross-sectional dimension of from 0.1 to 30 μm, the ratio ofgas to liquid being controlled such that a microfoam is produced havinga density of between 0.07 g/mL to 0.19 g/mL and a half-life of at least2 minutes.

[0031] Preferably the microfoam is such that 50% or more by number ofits gas bubbles of 25 μm diameter and over are no more than 200 μmdiameter.

[0032] Preferably the gas/liquid ratio in the mix is controlled suchthat the density of the microfoam is 0.09 g/mL to 0.16 g/mL. morepreferably 0.11 g/mL to 0.14 g/mL.

[0033] Preferably the microfoam has a half-life of at least 2.5 minutes.more preferably at least 3 minutes. The half-life may be as high as 1 or2 hours or more, but is preferably less than 60 minutes, more preferablyless than 15 minutes and most preferably less than 10 minutes.

[0034] Half-life is conveniently measured by filling vessel with a knownvolume and weight of foam and allowing liquid from this to drain into agraduated vessel, the amount drained in a given time allowingcalculation of half-life i.e. of conversion of microfoam back into itscomponent liquid and gas phases. This is preferably carried out atstandard temperature and pressure, but in practice ambient clinic orlaboratory conditions will suffice.

[0035] Advantageously and preferably the method provides a foamcharacterized in that at least 50% by number of its gas bubbles of 25 μmdiameter and over are of no more than 150 μm diameter, more preferablyat least 95% of these gas bubbles by number are of no more than 280 μmdiameter. Still more preferably at least 50% by number of these gasbubbles are of no more than 130 μm diameter and still more preferably atleast 95% of these gas bubbles by number are of no more than 250 μmdiameter.

[0036] Preferably the mixture of gas and sclerosant liquid is in theform of an aerosol, a dispersion of bubbles in liquid or a macrofoam. Bymacrofoam is meant a foam that has gas bubbles that are measured inmillimeters largest dimension. e.g. approximately 1 mm and over, andover such as can be produced by lightly agitating the two phases byshaking. Preferably the gas and liquid are in provided in the form of anaerosol where a source of pressurized gas and a means for mixing the twois provided to the point of use. It may be preferred that a macrofoam isfirst produced where the liquid and gas are brought together only at thepoint of use.

[0037] The ratio of gas to liquid used in the mixture is important inorder to control the structure of the microfoam produced such that itsstability is optimized for the procedure and the circumstances in whichit is being carried out. For optimum foams it is preferred to mix 1 gramsclerosant liquid with from approximately 6.25 to 14.3 volumes (STP),more preferably 7 to 12 volumes (STP), of gas.

[0038] Preferably the physiologically acceptable blood dispersible gascomprises a major proportion of carbon dioxide and/or oxygen.Conveniently it may comprise a minor proportion of nitrogen or otherphysiologically acceptable gas. While a proportion of nitrogen may bepresent, as in air, the present invention provides for use of carbondioxide and/or oxygen without presence of nitrogen.

[0039] In one preferred form the gas used is a mixture of carbon dioxideand other physiological gases, particularly containing 3% or more carbondioxide, more preferably from 10 to 90% carbon dioxide, most preferably30 to 50% carbon dioxide. The other components of this gas arepreferably oxygen with a minor proportion only of nitrogen beingpreferred. Most preferably the other component is oxygen.

[0040] A further preferred form of gas comprises 50% vol/vol or moreoxygen. the remainder being carbon dioxide, or carbon dioxide, nitrogenand trace gases in the proportion found in atmospheric air. Onepreferred gas is 60 to 90% vol/vol oxygen and 40 to 10% vol/vol carbondioxide, more preferably 70 to 80% vol/vol oxygen and 30 to 20% vol/volcarbon dioxide. More preferred is 99% or more oxvgen.

[0041] It is found that passing a stream of the sclerosant liquid andthe gas under pressure through one or more passages of 0.1 μm to 30 μmas described provides a stable blood dispersible gas based sclerosantinjectable microfoam that was previously thought to be only producibleby supply of high amounts of energy using high speed brushes andblenders.

[0042] Preferably the sclerosing agent is a solution of polidocanol orsodium tetradecylsulfate in an aqueous carrier. e.g. water, particularlyin a saline. More preferably the solution is from 0.5 to 5% v/vpolidocanol. preferably in sterile water or a physiologically acceptablesaline, e.g. in 0.5 to 1.5% v/v saline. Concentration of sclerosant inthe solution will be advantageously increased for certain abnormalitiessuch as Klippel-Trenaunay syndrome.

[0043] Polidocanol is a mixture of monolauryl ethers of macrogols offormula C₁₂H₂₅(OCH₂CH₂)_(n)OH with an average value of n of 9. It willbe realized that mixtures with other alkyl chains, oxyalkyl repeat unitsand/or average values of n might also be used, e.g. 7 to 11, but that 9is most conveniently obtainable, e.g. from Kreussler, Germany, e.g. asAethoxysklerol™.

[0044] Most preferably the concentration of sclerosant in the aqueousliquid is a 1-3% vol/vol solution, preferably of polidocanol, in wateror saline, more preferably about 2% vol/vol. The water or saline also,in some cases at least, preferably contain 2-4% vol/vol physiologicallyacceptable alcohol, e.g. ethanol. Preferred saline is buffered.Preferred buffered saline is phosphate buffered saline. The pH of thebuffer is preferably adjusted to be physiological, e.g. from pH 6.0 topH 8.0, more preferably about pH 7.0.

[0045] The sclerosant may also contain additional components, such asstabilizing agents, e.g. foam stabilizing agents. e.g. such as glycerol.Further components may include alcohols such as ethanol.

[0046] The aerosol, dispersion or macrofoam is preferably produced bymixing the gas and liquid from respective flows under pressure. Themixing conveniently is carried out in a gas liquid interface elementsuch as may be found in aerosol canisters. The interface device mayhowever be very simple, such as a single chamber or passage ofmillimeter dimensions, i.e. from 0.5 to 20 mm diameter, preferably 1 to15 mm diameter, into which separate inlets allow entry of gas andliquid. Conveniently the interface is of design which is commonly foundin aerosol canisters but which is selected to allow the correct ratio ofgas to liquid to allow formation of a foam of the presently defineddensity. Suitable inserts are available from Precision Valves(Peterborough UK) under the name Ecosol and are selected to produce theratio specified by the method above.

[0047] However, the mixing of gas and liquid may also be brought aboutwithin a dip-tube leading from the sclerosant solution located in thebottom of a pressurized container where holes in the dip-tube allow gasto enter into a liquid stream entering from the bottom of the tube. Inthis case the holes may be of similar diameter to the Ecosol holes. Suchholes may be conveniently produced by laser drilling of the dip-tube.

[0048] The one or more passages through which the aerosol or macrofoamso produced are passed to produce the stable microfoam preferably havediameter of from 5 μm to 15 μm, more preferably from 10 μm to 20 μmwhere simple passages are provided, such as provided by openings in amesh or screen. e.g. of metal or plastics, placed perpendicular to theflow of gas/liquid mixture. The passage is conveniently of circular orelliptical cross section, but is not necessarily so limited. A number ofsuch meshes or screens may be employed along the direction of flow.

[0049] Most preferably the passages are provided as multiple openings inone or more elements placed across the flow. Preferably the elements arefrom 2 to 30 mm diameter, more preferably 6 to 15 mm diameter, face onto the flow, with 5 to 65% open area, e.g. 2% to 20% open area for wovenmeshes and 20% to 70% open area for microporous membranes. Openings in aporous material, such as provided in a perforated body, preferablyprovide several hundreds or more of such passages, more preferably tensor hundred of thousands of such passages, e.g. 10,000 to 500,000,presented to the gas liquid mixture as it flows. Such material may be aperforated sheet or membrane, a mesh, screen or sinter. Still morepreferably a number of sets of porous material are provided arrangedsequentially such that the gas and liquid pass through the passages ofeach set. This leads to production of a more uniform foam.

[0050] Where several elements are used in series these are preferablyspaced 1 to 5 mm apart, more preferably 2 to 4 mm apart e.g. 3 to 3.5 mmapart.

[0051] For some embodiments of the present invention it is found thatthe passage may take the form of a gap between fibers in a fibrous sheetplaced across the path of the gas/liquid flow, and the dimensiondescribed in not necessarily the largest diameter, but is the width ofthe gap through which the gas/liquid aerosol or macrofoam must flow.

[0052] Alternatively the method provides for passing the mixture of gasand liquid through the same set of passages, e.g. as provided by one ormore such porous bodies, a number of times, e.g. from 2 to 2,000, morepreferably 4 to 200 times. or as many times as conveniently results in amicrofoam of the required density set out above. It will be realizedthat the more times the microfoam passes through the meshes, the moreuniform it becomes.

[0053] The pressure of the gas used as it is passed through the passageswill depend upon the nature of the mechanism used to produce the foam.Where the gas is contained in a pressurized chamber, such as in anaerosol canister, in contact with the liquid, suitable pressures aretypically in the range 0.01 to 9 bar over atmosphere. For use of meshes,e.g. 1 to 8 meshes arranged in series, having apertures of 10-20 μmdiameter, 0.1 to 5 bars over atmosphere will, inter alia, be suitable.For use of 3-5 meshes of 20 μm aperture it is found that 1.5-1.7 barover atmospheric is sufficient to produce a good foam. For a 0.1 μm poresize membrane, a pressure of 5 bar or more over atmospheric pressure ispreferred.

[0054] In one preferred form of the invention the passages are in theform of a membrane, e.g. of polymer such as polytetrafluoroethylene,wherein the membrane is formed of randomly connected fibers and has arated effective pore size which may be many times smaller than itsapparent pore size. A particularly suitable form of this is a biaxiallyoriented PTFE film provided by Tetratec™ USA under the trademarkTetratex™, standard ratings being 0.1 to 10 μm porosity. Preferred poresizes for the present method and devices are 3 to 7 μm. This materialmay be laminated with a porous backing material to give it strength andhas the advantage that one pass through may be sufficient to produce afoam that meets the use requirements set out above with regard tostability. However, it will evident to those skilled in the art that useof more than one such membrane in series will give a still more uniformfoam for given set of conditions.

[0055] It is believed that the combination of provision of a stream ofsolution and gas under pressure through an aerosol valve and then flowthrough the passages, e.g. pores in a mesh, screen, membrane or sinterprovides energy sufficient to produce a stable aqueous liquid solublegas, e.g. carbon dioxide and/or oxygen, based sclerosant microfoam thatwas previously thought to be only producible by supply of high amountsof energy using high speed brushes and blenders as described in theprior art.

[0056] Preferably the method of the invention provides a microfoamhaving at least 50% by number of its gas bubbles of 25 μm diameter orover being no more than 120 μm diameter. Preferably at least 95% of itsgas bubbles of 25 μm diameter or over are of no more than 250 μmdiameter. Diameter of such bubbles may be determined by the method setout in the Example 5 set out herein.

[0057] A most preferred method of the invention provides a housing inwhich is situated a pressurisable chamber. For sterile supply purposesthis will at least partly filled with a sterile and pyrogen freesolution of the sclerosing agent in a physiologically acceptable aqueoussolvent but otherwise may be charged with such at the point of use. Thisconvenient method provides a pathway by which the solution may pass fromthe pressurisable chamber to exterior of the housing through an outletand more preferably a mechanism by which the pathway from the chamber tothe exterior can be opened or closed such that when the container ispressurized, fluid will be forced along the pathway and through one ormore outlet orifices.

[0058] The method is particularly characterized in that the housingincorporates one or more of (a) a pressurized source of thephysiologically acceptable gas that is readily dispersible in blood, and(b) an inlet for the admission of a source of said gas; the gas beingcontacted with the solution on activation of the mechanism.

[0059] The gas and solution are caused to pass along the pathway to theexterior of the housing through the one or more, preferably multiple,passages of defined dimension above, through which the solution and gasmust pass to reach the exterior, whereby on contact with, e.g. flowthrough, the passages the solution and gas form a the microfoam.

[0060] Preferably the as and liquid pass through a gas liquid interfacemechanism, typically being a junction between a passage and one or moreadjoining passages, and are converted to an aerosol, dispersion ofbubbles or macrofoam before passing through the passages, but asexplained they may be converted first to a macrofoam, e.g. by shaking ofthe device, e.g. by hand, or mechanical shaking device.

[0061] In a second aspect of the present invention there is provided adevice for producing a microfoam suitable for use in scleropathy ofblood vessels, particularly veins, comprising a housing in which issituated a pressurisable chamber containing a solution of the sclerosingagent in a physiologically acceptable solvent referred to in the firstaspect; a pathway with one or more outlet orifices by which the solutionmay pass from the pressurisable chamber to exterior of the devicethrough said one or more outlet orifices and a mechanism by which thepathway from the chamber to the exterior can be opened or closed suchthat, when the container is pressurized and the pathway is open, fluidwill be forced along the pathway and through the one or more outletorifices

[0062] said housing incorporating one or more of (a) a pressurizedsource of physiologically acceptable as that is dispersible in blood and(b) an inlet for the admission of said gas; the gas being in contactedwith the solution on activation of the mechanism such as to produce agas solution mixture

[0063] said pathway to the exterior of the housing including one or moreelements defining one or more passages of cross sectional dimension,preferably diameter, 0.1 μm to 30 μm, through which the solution and gasmixture is passed to reach the exterior of the device, said passing ofsaid mixture through the passages forming a microfoam of from 0.07 to0.19 /mL density and of half-life at least 2 minutes.

[0064] Preferably the microfoam has 50% or more by number of its gasbubbles of 25 μm diameter and over of no more than 200 μm diameter.

[0065] More preferably the microfoam is from 0.09 to 0.16 g/mL densityand most preferably of 0.11 g/mL to 0.14 g/mL.

[0066] Preferably the microfoam has a half-life of at least 2.5 minutes,more preferably at least 3 minutes.

[0067] Advantageously and preferably this device provides a microfoamcharacterized in that at least 50% by number of its gas bubbles of 25 μmdiameter and over are of no more than 150 μm diameter or less, morepreferably at least 95% by number of these gas bubbles are of diameter280 μm or less. Still more preferably at least 50% by number of thesegas bubbles are of no more than 120 μm diameter and still morepreferably at least 95% of these gas bubbles are of no more than 250 μmdiameter.

[0068] Preferably the apparatus includes a chamber. e.g. such as in asealed canister, charged with the blood dispersible gas and thesclerosant liquid, e.g. in a single chamber, the device pathwayincluding a dip tube with an inlet opening under the level of the liquidin this chamber when the device is positioned upright. Preferably thedip-tube has an outlet opening at a gas liquid interface junction wherethe gas, which resides in the chamber above the liquid, has access tothe pathway to the device outlet. The pathway is opened or closed by avalve element which is depressed or tilted to open up a pathway to theexterior of the device, whereby the liquid rises up the dip tube undergas pressure and is mixed in the interface junction with that as toproduce an aerosol, dispersion of bubbles in liquid or macrofoam.

[0069] Either inside the pressurisable chamber disposed in the pathwayto the valve, or on the downstream side of the valve, is provided anelement having the one or more passages described in the first aspectmounted such that the gas liquid mixture, i.e. dispersion of bubbles inliquid, aerosol or macrofoam,, passes through the passage or passagesand is caused to foam. This element may conveniently be located in a capon the canister in between the valve mounting and an outlet nozzle.Conveniently depression of the cap operates the valve. Alternatively theelement is within the canister mounted above the gas liquid interface.

[0070] In an alternate embodiment of this device the gas liquidinterface may comprise holes in the dip tube above the level of theliquid in the canister inner chamber.

[0071] The gas pressure employed will be dependent upon materials beingused and their configuration, but conveniently will be 0.01 to 9 barover atmospheric, more preferably 0.1-3 bar over atmospheric, and stillmore preferably 1.5-1.7 bar over atmospheric pressure.

[0072] A preferred device of this aspect of the invention is of the‘bag-on-valve' type. Such device includes a flexible gas and liquidtight container, forming a second inner chamber within the pressurisablechamber, which is sealed around the dip-tube and filled with the liquid.More preferably the dip-tube has a one-way valve located at a positionbetween its end located in the sclerosant liquid and the gas liquidinterface junction, which when the passage to the exterior is closed,remains closed such as to separate the liquid from the physiologicallyacceptable blood dispersible gas around it in the chamber. On openingthe pathway to the exterior, the one way valve also opens and releasesliquid up the dip-tube to the gas liquid interface where an aerosol isproduced which is in turn then passed through the passages to beconverted to microfoam. A suitable one-way valve is a duck-bill typevalve, e.g. such as available from Vernay Labs Inc, Yellow Springs,Ohio, USA. Suitable bag-on-valve can constructions are available fromCoster Aerosols. Stevenage. UK and comprise an aluminum foil/plasticslaminate.

[0073] Conveniently the one way valve is located at the top of thedip-tube between that and the gas liquid interface junction, i.e. anEcosol device. This allows filling of the bag before application of theone way valve, followed by sterilization of the contents, whether in thecanister or otherwise.

[0074] Such a preferred device has several potential advantages. Whereoxygen is the gas, this is kept separate from the liquid before use andthus reduces possibility of oxygen radicals reacting with organiccomponents in the liquid, e.g. during sterilization processes such asirradiation. Where carbon dioxide is the gas, storage can lead to highvolumes of gas dissolving in the liquid, which on release to theatmosphere or lower pressure, could out-Las and start to destroy themicrofoam too quickly. Such separation also prevents the deposition ofsolidified sclerosing agent components in the dimension sensitiveorifices of the device in an unused can in storage or transit,particularly should that be oriented other than upright.

[0075] It is preferred that the gas liquid interface is provided as adefined orifice size device such as the Ecosol device provided byPrecision Valve Peterborough UK. For a device where the passages ofdefined dimension are outside of the pressurized chamber, i.e. mountedon the valve stem, the ratio of area of the gas holes to the liquidholes should be of the order of 3 to 5, preferably about 4. Where thepassages are inside the pressurized chamber this is preferably higher.

[0076] A third aspect of the invention provides a device for producing amicrofoam suitable for use in sclerotherapy of blood vessels,particularly veins, comprising a housing in which is situated apressurisable chamber, at least part filled or fillable with a solutionof a sclerosing agent in a physiologically acceptable solvent and/or aphysiologically acceptable blood dispersible as a pathway by which thecontents of the chamber may be passed to exterior of the housing throughone or more outlet orifices and a mechanism by which the chamber can bepressurized such that its contents pass to the exterior alone thepathway and through one or more outlet orifices

[0077] said pathway to the exterior of the housing or the chamberincluding one or more elements defining one or more passages of crosssectional dimension, preferably diameter, 0.1 μm to 30 μm through whichthe contents of the chamber may be passed, whereby on passing throughthe passages the solution and as form a microfoam of from 0.07 to 0.19g/mL density and having a half-life of at least 2 minutes.

[0078] Preferably the microfoam is such that 50% or more by number ofits gas bubbles of 25 μm or more diameter are of no more than 200 μmdiameter.

[0079] Preferably the microfoam is of density 0.09 to 0.16 g/mL and morepreferably of 0.11 g/mL to 0.14 g/mL. The preferred limits on bubblesize are also as for the first and second aspects.

[0080] Preferably the microfoam has a half-life of at least 2.5 minutes,more preferably at least 3 minutes

[0081] The elements defining the passages in the pathway or chamber maybe static or may be moveable by manipulation of the device from outsideof its interior chamber.

[0082] Preferably the housing is a container definings a chamber inwhich is situated the solution and gas under pressure and the pathway isa conduit leading from the chamber in the interior of the container to avalve closing an opening in the container wall.

[0083] Preferred forms of the one or more elements defining the multiplepassages for use in the device of the present invention are meshes,screens or sinters. Thus one or more meshes or perforated screens orsinters will be provided, with some preferred forms employing a seriesof such elements arranged in parallel with their major surfacesperpendicular to the path of solution/as expulsion.

[0084] It is preferred that all elements of any of the devices accordingto the invention having a critical dimension are made of a material thatdoes not change dimension when exposed to aqueous material. Thuselements with such function such as the air liquid interface and theelement defining the passages of 0.1 μm-30 μm dimension preferablyshould not be of a water swellable material such as Nylon 66 where theyare likely to be exposed to the solution for more than a few minutes.Where such exposure is likely these parts are more preferably beingfashioned from a polyolefin such as polypropylene or polyethylene.

[0085] Preferably the canister is sized such that it contains sufficientgas and solution to form up to 500 mL of microfoam, more preferably from1 mL up to 200 mL and most preferably from 10 to 60 mL of microfoam.Particularly the amount of gas under pressure in such canisters shouldbe sufficient to produce enough foam to treat, i.e. fill, at least onevaricosed human saphenous vein. Thus preferred canisters of theinvention may be smaller than those currently used for supply ofdomestic used mousse type foams. The most preferred canister device isdisposable after use, or cannot be reused once opened such as to avoidproblems of maintaining sterility.

[0086] It may be preferred to incorporate a device which maintains gaspressure in the canister as foam is expelled. Suitable devices are suchas described under trademarked devices PECAP and Atmosol. However, wherea significant headspace or pressure of as is provided this will not benecessary.

[0087] In order to ensure that the microfoam delivered from devices ofthe invention is not ‘outside’ specification, i.e. falls within thedesired density, bubble size and half life parameters set out above, thepresent invention provides a further, fourth aspect which provides adevice which is positioned to receive microfoam emitted from the deviceof the second and third aspects of the invention, which device allowsventing of the first portion of microfoam to waste and passage of asecond portion of microfoam to a delivery device, such as a syringe, insterile fashion.

[0088] A device of the fourth aspect comprises an inlet conduit beingadapted to engage the outlet of a microfoam producing device of thesecond or third aspect in a microfoam tight fashion, the conduit beingconnected to and leading through a multipath tap capable of being set todirect microfoam passing down the conduit to one or both of first andsecond contiguous outlet conduits or to close the inlet conduit, atleast one of the first and second outlet conduits being adapted toreceive the luer connector of a syringe. Preferably the device alsocomprises one or more elements for engaging the device of the second orthird aspect other than by its outlet nozzle to hold it securely, e.g.upright in the case of a canister with a dip-tube.

[0089] Preferably the device of the fourth aspect comprises a three-waytap. More preferably the device of the fourth aspect comprises a baseelement, sufficiently stable to mount a microfoam producing device ofthe second or third aspects when engaged thereby. Preferably themicrofoam producing device is engaged by resilient elements which locateit securely adjacent the three-way tap whereby the inlet conduit can beattached to the microfoam producing device outlet conduit.

[0090] Particularly preferred the device of the fourth aspect comprisesa base element adapted mount the microfoam dispensing device and anactivating element which operates to cause the pathway to be opened theto the inlet conduit. In this manner when the multi-way tap is shut, thedispensing device contents remain therein, but when the multi-way tap isopened to either of its outlet conduits it immediately causes release offoam generated by the device.

[0091] A further aspect of the present invention provides improvedmicrofoams for use in the elimination of blood vessels and vascularmalformations that are made available by the method and devices of theinvention characterized in that they comprise a physiologicallyacceptable gas that is readily dispersible in blood together with anaqueous sclerosant liquid characterized in that the microfoam has adensity of from 0.07 to 0.19 g/cm³ and is capable of being passed down a21 gauge needle without reverting back to gas and liquid by more than10%, based on liquid content reverting back to unfoamed liquid phase.

[0092] Preferably the microfoam, on passage through said needle, doesnot revert back to unfoamed liquid by more than 5% based on liquidcontent. still more preferably by no more than 2%.

[0093] Preferably the microfoam is capable of being passed down a needlewhile retaining at least 50% by number of its gas bubbles of at least 25μm diameter at no more than 200 μm diameter. This is convenientlymeasured under ambient conditions, more preferably at STP.

[0094] Preferably at least 50% by number of said gas bubbles remain atno more than 150 μm diameter and at least 95% of these bubbles at nomore than 280 μm diameter. Preferably the microfoam has a half-life asmeasured by drainage through a funnel of 2 cm neck diameter and drainagepath 10 cm of at least 2 minutes, more preferably 2.5 minutes and mostpreferably 3 minutes. This may be carried out at ambient temperature orSTP. Most conveniently the funnel is pre-equilibrated in a water bath toensure a temperature of 25° C. before drying and application of foam.Placing of a microfoam filled syringe upside down, without its plunger,above the funnel leading into a graduated receptacle allows convenientmeasurement of this parameter.

[0095] Preferably the gas includes less than 40% v/v nitrogen.Preferably the density of the microfoam is from 0.09 to 0.16 g/L, morepreferably 0.11 g/mL to 0.14 g/mL.

[0096] Advantageously and preferably at least 50% by number of the gasbubbles of 25 μm diameter or more are of no more than 120 μm diameterand still more preferably at least 95% of these gas bubbles are ofdiameter 250 μm or less.

[0097] Preferably the foam density, which is a measure of liquid/gasratio is from 0.13 to 0.14 g/cm³ and the half-life is at least 2.5minutes. The foam more preferably does not move outside of itsparameters of bubble size set out above in such time.

[0098] Preferably the gas consists of at least 50% oxvgen or carbondioxide, more preferably 75% or more oxygen or carbon dioxide and mostpreferably at least 99% oxvgen or carbon dioxide, e.g. substantially100% oxven or carbon dioxide. Preferably the oxvgen or carbon dioxide ismedical grade.

[0099] Preferably the sclerosant is aqueous polidocanol or sodiumtetradecyl sulfate.

[0100] When the sclerosant is aqueous polidocanol the concentration ofpolidocanol is from 0.5 to 4% vol/vol in the liquid, preferably being 1to 3% vol/vol polidocanol and most preferably being 2% vol/vol in theliquid.

[0101] Advantageously the sclerosant is made up in water, but moreadvantageously is made up in a saline solution, particularly 10 to 70 mMphosphate buffered saline, e.g. 50 mM phosphate buffered saline, andpreferably of pH 6 to pH 8.0 e.g. about pH 7.0. Advantageously theaqueous solution contains a minor amount of an alcohol, preferably 96%ethanol. e.g. at between 2 and 6% vol/vol, more preferably at about 4%vol/vol of 96% ethanol.

[0102] Addition of glycerol to the aforesaid sclerosant imparts a longerhalf-life to the resultant foam. However, glycerol also produces atendencv for the meshes to block up when using a mesh device asdescribed above, so should be used carefully where the device it isproduced from may be used multiple times or the bag-on-valve concept isused.

[0103] The present invention will now be described further by way ofillustration only by reference to the following Figures and Examples.Further embodiments falling within the scope of the invention will occurto those skilled in the art in the light of these.

FIGURES

[0104]FIG. 1: Shows a cross-sectional view of a canister device of thesecond aspect of the invention as further described in Example 2 below.

[0105]FIG. 2: Shows a cross-sectional view of a canister device of thesecond aspect incorporating a bag-on-valve reservoir for the sclerosantwith the gas being in the outer chamber and separated therefrom by a oneway duck-bill valve.

[0106]FIG. 3: Is a bar chart and graph illustrating distribution of asbubble diameter in a preferred 0.13 g/mL oxygen/air/polidocanolmicrofoam of the fourth aspect.

[0107]FIG. 4: Is a graph illustrating distribution of as bubble diameterin microfoams of 0.09 g/mL and 0.16 g/mL of the fourth aspect.

[0108]FIG. 5: Is a graph showing the effect of passing a preferred foamof the fourth aspect down a 21 gauge needle as compared to control freshand similarly aged microfoams.

[0109]FIG. 6: Is a bar chart and graph showing the effect of passing a2% vol polidocanol solution dry microfoam of density 0.045 g/mL , suchas producible by use of a prior art bubbler device (Swedspray valve.Ecosol insert and head), down a 21 gauge needle.

[0110]FIG. 7: Is a graph showing the effect of passing a 1% volpolidocanol dry microfoam of density 0.045 g/mL such as producible byuse of the prior art bubbler device (Swedspray valve. Ecosol insert andhead), down a 21 gauge needle.

[0111]FIG. 8: is an elevation view of a syringe filling device of thefourth aspect.

[0112]FIG. 9: Is a plan view of the device of FIG. 8.

EXAMPLES Example 1

[0113] A standard aerosol canister with a one way depressible actionvalve is charged half full with a 3% v/v solution of polidocanol insterile water and pressurized to 3 atmospheres with a 50:50 mix ofcarbon dioxide and oxygen. On the valve stem is mounted an actuator anddelivery head which carries four plastics screens, just under 0.5 mmthick, perforated with 20 μm diameter passages, these screens being ofthe general type provided in the Swedspray-Eurospray foaming actuatorcap ApRisC™ device. The valve is fed through an Ecosol gas liquidinterface insert from a dip-tube and the surrounding chamber. Gas inletsizes (×2) into the insert are 0.006″×0.01″ while the single liquidinlet is 0.024″, as controlled by selecting Ecosol insert size. Ondepression of the head the aerosol valve releases pre-mixed solution andgas onto the screens whereupon a microfoam suitable for scleropathy andthat is dimensionally stable for at least 2 minutes, preferably 5minutes using glycerol in the polidocanol solution is produced.

Example 2

[0114]FIG. 1 illustrates a further canister design of the inventionwherein the passages through which the gas liquid mixture must travelare placed within the pressurized chamber, thus increasing hygiene ofthe device.

[0115] The canister is of standard 500 mL design with an aluminum wall(1), the inside surface of which is coated with an epoxy resin resistantto action of polidocanol and oxygen (e.g. Hoba 7940—Holden UK)). Thebottom of the canister (2) is domed inward. The canister inner chamber(4) is pre-purged with 100% oxygen for 1 minute, containing 15 mL of a2% vol/vol polidocanol/20 mmol phosphate buffered saline solution (3)then filled with the oxygen at 2.7 bar gauge (1.7 bar over atmospheric).This is provided by overpressuring the polidocanol part filled can with1.7 bar oxygen.

[0116] The dome provides a perimeter area around the bottom of the innerchamber in which a level of polidocanol solution is retained sufficientfor the bottom open end of a dip tube to be submerged therein when thetop of the dome is no longer covered with the solution. In this manner,by use of an indicia on the outside of the canister to indicate theposition of the dip tube, the canister can be oriented to extract thelast fraction of solution if desired. In practice a vertical orientationis sufficient.

[0117] A standard 1″ diameter aerosol valve (5) (Precision Valves,Peterborough) is crimped into the top of the canister after sterile partfilling with the solution and is activatable by depressing an actuatorcap (6) to release content via an outlet nozzle (13) sized to engage aluer fitting of a syringe or multi-way connector (not shown). A furtherconnector (7) locates on the bottom of the standard valve and mounts,preferably by interference fit, four Nylon 66 meshes held in highdensity polyethylene (HDPE) rings (8) all within an open endedpolypropylene casing. These meshes have diameter of 8 mm and have a 15%open area made up of 20 μm pores, with the meshes spaced 3.5 mm apart bythe HDPE rings.

[0118] A further connector (9) locates on the bottom of the connectorholding the meshes and receives a housing (10) which mounts the dip tube(12) and includes gas receiving holes (11 a, 11 b) which admit gas fromchamber (4) into the flow of liquid which rises up the diptube onoperation of the actuator (6). These are conveniently defined by anEcosol device with insert as before. Holes (11 a, 11 b) havecross-sectional area such that the sum total ratio of this to thecross-sectional area of the diptube is controlled to provide therequired gas/liquid ratio. This is for example 0.010″×0.013″ each hole(11 a, 11 b) to 0.040″ liquid receiving hole.

Example 3

[0119] A further canister embodiment of the present invention is shownin FIG. 2, which is broadly as shown in FIG. 1, but for the inclusion ofa modified ‘bag-on-valve’ arrangement. In this embodiment thepolidocanol sclerosing solution (3) is enclosed in a foil bag (22),comprising an aluminum foil/plastics laminate (Coster Aerosols StevenageLTK) sealed in gas tight fashion to dip-tube (12). At the top end of thedip-tube is a one-way duck-bill valve (Vernay Labs Inc Ohio USA) thatserves to prevent contact of polidocanol with the contents of thedip-tube (12) and chamber (4) until the valve (5) is operated. On saidoperation the valve (21) opens and polidocanol solution (3) is caused torise up the dip-tube (12), whereby it becomes mixed with the air/oxygengas mixture entering through holes (11 a, 11 b). In this manner the canmay be safely sterilized with ionizing radiatons which may otherwisecause interactions between radical species in the gas and the organiccomponent of the polidocanol solution. Such arrangement can also improvethe operation of the canister with regard to start up of foam delivery.The bag (22) preferably substantially only contains the liquid (3), withno head-space gas above it.

Example 4

[0120] The device of this example is identical with that of Example 3,save that the polidocanol in the liquid is replaced with a sodiumtetradecylsulfate at 1% vol/vol, all other ingredients being the same.

Example 5

[0121] A microfoam of the invention is produced in a device as describedin Example 1, having critical passage and gas mixing dimensions as setout in Example 2 but differing therefrom in that mesh is located in thedispensing cap, downstream of the valve, while gas/liquid mixing occursin an Precision Valves Ecosol insert device upstream of the valve. Thechamber (500 mL) is charged with 15 mL of an aqueous solution containingper 100 mL polidocanol (Kreussler—Germany) (2 mL), 96% ethanol (4 mL)and 55 mmol Phosphate Buffer (pH 7.0) (94 mL) with gas being airoverpressured with 1.5 bar 100% oxygen. The characteristics of themicrofoam produced on operation of the valve are shown in FIGS. 3 and 4.FIG. 3 shows bubble size distribution immediately after microfoamgeneration; foam density being 0.138 g/mL. FIG. 4 shows bubble sizeproduced with varying ratio of gas to liquid, provided by altering theas/liquid interface hole size (11 a, 11 b) to give foams of 0.09 g/mL(diamonds) and 0.16 /mL (squares). FIG. 5 shows the effect on bubblesize distribution of a preferred microfoam (0.13 g/mL) after passagethrough a 21 G needle: Squares show fresh foam, diamonds control foamaged to match injection time and triangles show after passage throughthe needle. FIG. 6 shows the effect of passing a microfoam made using aSwedspray device density 0.045 g/mL through the needle. Closed diamondsare control aged while open circles are after needle passage.

[0122] Note, when 5% glycerol is added to the formulation, half life wasincreased to approximately 4 minutes.

[0123] Bubble sizes are calculated by taking up foam into a syringethrough its luer opening, optionally attaching a 21 G needle, andinjecting foam between two glass slides that are separated using 23.25micron diameter beads (e.g. available as microspheres from Park LabsUSA). Maxtascan/Global Lab Image technique was used to analyze bubblesize. Diameters of uncompressed bubbles (Dr) were calculated fromdiameters of bubbles between slides (Df) using the equation:${Dr} = {{\sqrt[3]{\frac{3}{2}{Df}^{\quad 2}}}^{\vartriangleright}x}$

[0124] where x is the distance between the slides. These measurementsthus are made at ambient temperature and pressure.

[0125] It will be realized that bubbles much smaller than 25 μm diametermay be present but not counted. The % figures given with respect tobubble thus relate to bubbles in the range 25 μm and above.

Example 6

[0126] For filling of a syringe with microfoam of the invention thebottom of a canister of Example 1, 2 or 3 is placed into a receivingrecess in the base of a syringe filling device as shown in elevation inFIG. 8 and plan (FIG. 9). Canister (24) is inserted into a 1 cm deeprecess (25) in a plastics base element (26), the recess beingapproximately 1 mm in diameter more than the canister such that a snugfit is provided. The canister is further supported by two resilientfixed arms (27 a, 27 b), fixed on vertical support rod (28) that deformto receive the canister diameter.

[0127] Just above the top of the position of the canister cap in use,the support rod (28) mounts an actuator arm that is lockable between afirst actuating position (full lines) an and an off position (dottedlines). In the actuating position the arm depresses the canisteractuator cap (30), thus opening the canister valve and causing microfoamto be released.

[0128] Also on the base (26) is a recess (32) sized to snugly receive asyringe (34) with its plunger. A stop element (33) is provided that ispositioned such that on filling the plunger is limited in its range oflongitudinal movement such that the syringe cannot be overfilled.

[0129] A flexible transparent plastics tube (35), inert to thesclerosant foam, is attached to the canister outlet nozzle (31) in useand is fixed to a three way valve (36) affixed to the base (26). Thevalve is operated by turning a tap (37) to one of three positions: (a)valve shut—no microfoam passage (b) valve open to waste (38) whereby anymicrofoam that by visual inspection of the contents of tube (35) appearsunsuitable, is vented and (c) valve open to syringe, whereby a setamount of microfoam passes through the syringe luer and fills it untilthe syringe plunger abuts the stop (33)

Example 7

[0130] 20 mL microfoam of Example 6 is loaded into a 20 mL syringe usingthe device of Example 6 and the syringe disengaged from the device. A 19gauge needle is attached either directly to the syringe luer fitting orvia a catheter. The microfoam is administered into to a varicose veinwhile its advance and final position is monitored using a hand heldultrasound scanner such that the fresh foam is restricted in location tothe vein being treated. After between 1 and 5 minutes the vein contractsand subsequently becomes fibrosed.

1. A microfoam comprising a physiologically acceptable gas that isdispersible in blood and an aqueous sclerosant liquid characterized inthat the microfoam has a density of from 0.07 to 0.19 g/cm³ and iscapable of being passed down a 21 gauge needle without reverting back togas and liquid by more than 10%, based on liquid content reverting backto unfoamed liquid phase.
 2. A microfoam comprising a physiologicallyacceptable gas that is dispersible in blood and an aqueous sclerosantliquid characterized in that the microfoam has a density of from 0.07 to0.19 g/cm³ and is capable of being passed down a 21 gauge needle suchthat 50% or more by number of its gas bubbles of at least 25 μm remainat 150 μm diameter or less and at least 95% of these bubbles at 280 μmdiameter or less.
 3. A microfoam as claimed in claim 1 or claim 2characterized in that it has a half-life as measured by drainage througha funnel of 1 cm neck diameter of at least 2 minutes, more preferably2.5 minutes and most preferably 3 minutes:
 4. A microfoam as claimed inany preceding claim characterized in that the gas includes less than 40%v/v nitrogen.
 5. A microfoam as claimed in any preceding claimcharacterized in that the density is from 0.09 to 0.16 g/mL.
 6. Amicrofoam as claimed in any preceding claim characterized in that 50% ormore by number of the gas bubbles of at least 25 μm diameter are of nomore than 120 μm diameter and at least 95% of these gas bubbles are ofno more than 250 μm.
 7. A microfoam as claimed in any preceding claimcharacterized in that it is of density of from 0.11 to 0.14 g/cm³.
 8. Amicrofoam as claimed in any preceding claim characterized in that thegas comprises at least 50% oxygen or carbon dioxide.
 9. A microfoam asclaimed in any preceding claim characterized in that the sclerosantliquid is aqueous polidocanol or sodium tetradecyl sulfate.
 10. Amicrofoam as claimed in claim 9 characterized in that the sclerosant isaqueous polidocanol, the concentration of polidocanol being is from 0.5to 4% vol/vol in the liquid.
 11. A microfoam as claimed in claim 9 orclaim 10 characterized in that sclerosant is made up in water or salinesolution.
 12. A microfoam as claimed in claim 11 characterized in thatthe saline is phosphate buffered saline pH 6.0 to pH 8.0.
 13. Amicrofoam as claimed in claim 10, 11 or 12 characterized in that theaqueous solution contains a minor amount of alcohol.
 14. A microfoam asclaimed in any preceding claim characterized in that it contains 1 to10% vouvol glycerol.
 15. A method of treating a patient in need ofsclerotherapy of a blood vessel comprising administering a microfoam asclaimed in any preceding claim to that blood vessel.